It is difficult to find effective treatments for rare diseases such as tuberous sclerosis because the patients are scattered all across the world and cared for by a large number of doctors who often have little expertise in the disease. The objectives of this project are to develop methods to focus both the care of patients and research in the disease regional centers, to 'nurture' the development of more expert clinicians, to maintain patient populations 'at the ready' for trials by collecting information in an organized way and at pre-specified intervals, to optimize the design of clinical trials for small patient numbers, and to reach answer in trials more quickly.

Tuberous sclerosis is a rare disease that can cause seizures, impairment in thinking, and benign tumors in the brain, skin, eye, and kidney. Lymphangioleiomyomatosis or LAM is the lung manifestation of tuberous sclerosis, which occurs in about 40% of women who have the disease. LAM also occurs in women who do not have tuberous sclerosis, but even in those cases it is caused by the same type of genetic mistakes that cause tuberous sclerosis. These errors cause 'short circuits' in the communication networks of the cell, and cause them to lose control over their growth. Our understanding of how these circuits are wired has grown tremendously in the last few years, and there are now many good ideas for drugs to test in LAM and tuberous sclerosis.

The underlying problems in the cell are similar in LAM and TSC, so it is very likely that discoveries made in LAM will benefit patients with other manifestations of tuberous sclerosis, and vice versa. Testing in animals can get us only so far, especially since mice with tuberous sclerosis do not develop most of the same problems as humans with tuberous sclerosis. Most experts agree that the fastest route to an effective treatment for LAM and tuberous sclerosis is through properly conducted clinical trials in humans. Put another way, we will most likely never find an effective treatment if patients do not enroll in trials.

With so many promising drugs to test, we need to find a way to do trials more quickly and one after the other. Patients with lung disease cannot easily travel long distances, and so the trial must come to the patient. The LAM Foundation has already established regional LAM clinics across the United States; this proposal will develop those LAM Clinics into a research network to perform trials together. All the information generated in the network will be funneled to a Data Center in Florida, where it will be collected and analyzed. Two initial projects are planned, one is to develop a blood test that can be used to make the diagnosis of LAM and to follow the effect of treatment, and the other is a trial of a drug that blocks the effect of estrogen in LAM. This proposal focuses on trials in LAM for several important reasons. Like the tuberous sclerosis community, LAM patients are organized and regional specialty clinics have already been established. However, because LAM is one of the most progressive and life-threatening manifestations of tuberous sclerosis, adults with LAM (with or without tuberous sclerosis) tend to be motivated to enroll in trials. That was a clear lesson from the first two trials in tuberous sclerosis and LAM, called CAST and MILES. As mentioned above, in general, advances for LAM are also advances for tuberous sclerosis. We believe that there should be a trial for every LAM patient, and every LAM patient should be in a trial. Successful completion of this proposal will define a new approach to clinical research in rare diseases, which may be applicable to many other disorders.